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Embryo/fetal–maternal cross talk
Published in Carlos Simón, Linda C. Giudice, The Endometrial Factor, 2017
Nuria Balaguer, Francisco Dominguez, Carlos Simón, Felipe Vilella
To understand the functional role of maternal miR-30d incorporation into the embryo, transcriptomic studies were used to compare the effects of mimic miR-30d miRNA and scramble miRNA in murine embryos. Expression arrays demonstrated that embryos treated with miR-30d have increased expression of 10 genes, including those encoding adhesion molecules such as ITGB3, ITGA7, and CDH5 (Figure 19.2). The induction of this adhesive phenotype was validated in vitro by adhesion assays showing a significant increase in the adhesion of murine embryos and human trophoblastic cell lines treated with miR-30d mimic versus miR-30d inhibitor. Further studies are needed to understand the underlying molecular mechanisms that enhance this adhesion phenotype. However, this work paves the way to understanding more accurately how the intrauterine environment is important not only in the attainment of a pregnancy but also in the epigenetic reprogramming to which the embryo is exposed throughout its different developmental stages.
Fibroids and Endometrial Receptivity/Embryo Implantation
Published in Botros R.M.B. Rizk, Yakoub Khalaf, Mostafa A. Borahay, Fibroids and Reproduction, 2020
Kamaria C. Cayton Vaught, Maria Facadio Antero, Jacqueline Y. Maher, Chantel I. Cross
Fibroids can impact endometrial gene expression through varying means (Table 3.2). As introduced earlier in this section, fibroids can alter gene expression indirectly by increasing the secretion of the cytokine TGF-β3, which then causes the downregulation of BMPR-2 expression within the endometrium [54,57]. Direct regulation of gene expression by fibroids can also occur and appears to be spatially regulated. The homeobox genes are critical for embryo implantation and have been discussed in detail. The presence of submucosal fibroids but not intramural fibroids decreases the expression of HOXA10. In contrast to Rackow and Taylor [40], Unlu et al. found the reverse to be true [63]. They investigated genes known to be important for endometrial receptivity (HOXA10, HOXA11, and ITGAV) in infertile women with either submucosal fibroids, intramural fibroids (noncavitary distorting), or a uterine septum before and after myomectomy compared to controls [63]. There was a trend in decreased mRNA expression in HOXA10, HOXA11, and ITGAV in women with submucosal or intramural fibroids that was not significant compared to controls. However, in women with intramural fibroids after myomectomy, there was a significant 12.8-fold and 9-fold increased expression of HOXA10 and HOXA11, respectively. Although nonsignificant, there was also a 26-fold increase in LIF expression and 15.9-fold increase in ITGB3 expression. Together their data suggest that there is a positive regulatory effect of gene expression after myomectomy of intramural fibroids. Conversely, they did not find a significant increase in mRNA expression after myomectomy in women with submucosal fibroids [63].
Mother and Embryo Cross Communication during Conception
Published in Carlos Simón, Carmen Rubio, Handbook of Genetic Diagnostic Technologies in Reproductive Medicine, 2022
Anna Idelevich, Andrea Peralta, Felipe Vilella
In the growing field of embryo–mother cross communication, EVs attracted interest only recently. Data have accumulated showing a key role of EVs at preconception from gamete maturation to implantation and throughout pregnancy [94]. Ng et al. first described the production of EVs by the human endometrial epithelial cell line ECC1 containing a specific subset of micro-RNAs (miRNAs), not detectable in parent cells [95] and later verified to be present in human uterine fluid. Burns et al., demonstrated the presence of EVs in the uterine fluid of pregnant sheep, positive for exosomal markers CD63 and HSP70, containing small RNAs (sRNAs) and miRNAs [96]. Greening et al. demonstrated that the proteome of highly purified exosomes from human endometrial epithelial cells is subject to steroid hormonal regulation—estrogen and progesterone—and varies with the menstrual cycle [97]. Villela et al. performed an elegant study showing internalization of has-miR30d by mouse embryos via the trophectoderm, resulting in an indirect overexpression of adhesion-related genes, namely Itgb3, Itga7, and Cdh [98]. In this study, treatment of mouse embryos with miR-30d resulted in increased embryo adhesion [98]. The same group also showed that miR-30d deficiency results in contrasting implantation rate reduction and impaired fetal growth [99], and heterogeneous nuclear ribonucleoprotein C1 (hnRNPC1) has been implicated in the mechanism of cell-to-cell communication [100]. These findings support a model in which maternal endometrial miRNAs act as transcriptomic modifiers of the preimplantation embryo. Analysis of human endometrial liquid biopsy (ELB) material in both natural, and hormonal replacement therapy (HRT) cycles revealed a panel of differentially expressed miRNAs, including members of the miR-30 family [101]. Recently, embryos were shown to “talk back” via release of progesterone-induced protein (PIBF) packaged in EVs, modulating the maternal immune response [11,102]. The presence of EVs in the uterine fluid implies endometrium–embryo crosstalking, although these studies require further, thorough exploration.
Maximum likelihood approach suggests positive selection in platelet integrin αIIbβ3 in mammalian species
Published in Platelets, 2019
Luís Bernardo Pina-Cabral, Miguel Carneiro, Begoña Criado, Pedro José Esteves
The coding sequence for ααIIb-subunit is located on the long arm (q) of chromosome 17 (17q21.32), spanning 17324 bp. This gene (ITGA2B) contains 30 exons that will yield a single polypeptide precursor with 1039 residues which will undergo proteolytic cleavage into a heavy (871 residues) and a light chain (137 residues) linked by a disulfide bond. This mature protein is composed of 1008 residues [15,16]. The coding sequence for β3-subunit (ITGB3 gene) is adjacent to the ITGA2B gene on chromosome 17, spanning 58870 bp. It is composed of 15 exons that will yield a protein precursor with 788 residues. After an initial cleavage of 26 residues, the mature protein with 762 residues joins αIIb-subunit to form integrin αIIbβ3 which is incorporated into the membranes in its inactivated state [17,18]. The complete sequences of mature integrins αIIb and β3 from 10 mammalian species were retrieved from GenBank (see Figures 1 and 2) and were aligned using BioEdit software version 7.2.0 [19].
Genetics of platelet traits in ischaemic stroke: focus on mean platelet volume and platelet count
Published in International Journal of Neuroscience, 2019
Kanika Vasudeva, Anjana Munshi
Population-specific and/or rare variants not detected by GWAS is captured by exome sequencing. It allows the identification of low-frequency variants that influence the complex phenotypes [111, 112]. Exome sequencing in 761 African Americans (NHLBI GO ESP Cohort) was performed with the imputation of discovered SNPs in 13,959 African Americans, found strongest association signal for PLT from rs17292650. It is an African ancestry-specific missense mutation (c.117G > T) [p.Lys39Asn] in exon 2 of MPL, that encodes thrombopoietin receptors on platelets and megakaryocytes. MPL variant has also been previously identified as a candidate essential for thrombosis. Genotyping of rs17292650 in a subset of 1,872 African American participants (WHI cohort) confirmed the association of minor allele of c. 117G > T with higher PLT. Furthermore, two coding variants in MPV (c.754T > C) [p.Tyr252His] and CD36 c.975T > G [p.Tyr325*] were found to be independently associated with lower PLT. Variants within CD109, CD6, ITGB3 (c.557C > T) gene, which encodes several platelet surface glycoprotein involved in platelet adhesion and aggregation as well as platelet alloantigen formation, have also been reported to affect the platelet formation and reactivity [69]. However, extensive application of exome sequencing is limited due to high expenditures and strenuous analytical and technical requirements.
High-throughput measurement of human platelet aggregation under flow: application in hemostasis and beyond
Published in Platelets, 2018
Sanne L. N. Brouns, Johanna P. van Geffen, Johan W. M. Heemskerk
Platelets from patients with bleeding and Glanzmann’s thrombasthenia, carrying loss-of-function mutations in the ITGA2B or ITGB3 genes, are characterized by absence of integrin αIIbß3 or a qualitative defect of integrin activation and, hence, inability to aggregate. Affected aggregate formation and integrin activation in Glanzmann patients has also been observed using flow assays assessing platelet adhesion and thrombus formation on collagen and other surfaces, independent of shear rate (15,42). Similarly, patients with a combined immune disease and bleeding disorder, i.e., leukocyte adhesion deficiency-III, due to homozygous dysfunctional mutations in FERMT3 (a gene coding for the integrin-regulating protein kindlin-3), have platelets that are unable of αIIbß3 activation and aggregation. High-throughput flow assays with blood from such a patient or the heterozygous parents showed a marked reduction for all parameters of thrombus formation on collagen-I and other surfaces (30).